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Riociguat in Children With Pulmonary Arterial Hypertension (PAH) (PATENT-CHILD)

Primary Purpose

Hypertension, Pulmonary

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Riociguat (Adempas, BAY63-2521)
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertension, Pulmonary focused on measuring Pulmonary arterial hypertension

Eligibility Criteria

6 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Children from 6 years to less than 18 years of age with pulmonary arterial hypertension (PAH)

  • Diagnosed with PAH :

    • Idiopathic (IPAH)
    • Hereditable (HPAH)

    • PAH associated with (APAH)

      • Connective tissue disease
      • Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery)

Regardless of the type of PAH, the following findings are not exclusionary:

--- Patent foramen ovale (PFO) and asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 cm (both confirmed by echocardiogram) and not associated with hemodynamic alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 are not exclusionary

  • PAH diagnosed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery)
  • PAH confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) ≥25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >240 dyn•sec•cm^-5 (i.e., ≥3.0 wood units•m^2)
  • Patients must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit.

Two groups of patients will be included:

  • Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) who need additional treatment (discretion of the investigator)

  • Incident: Treatment naïve patients initiated on PAH medication (allowing ERA and /or PCA) and then riociguat added once patients are stable on standard of care

    • WHO functional class I-III
    • Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to receive sexual counseling and use effective contraception as applicable. 'Effective contraception' is defined as progestogen-only hormonal contraception associated with inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or any combination of adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to use contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration.
    • Young men must agree to use adequate contraception when sexually active.
    • Written inform consent provided and if applicable child assent provided

Exclusion Criteria:

  • Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in any form

    -- Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1. The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion.

  • Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening
  • Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004)
  • History of left-sided heart disease, including valvular disease or heart failure
  • Pulmonary hypertension related to conditions other than specified in the inclusion criteria
  • WHO functional class IV
  • Pulmonary veno-occlusive disease
  • Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN)
  • Severe restrictive lung disease
  • Severe congenital abnormalities of the lung, thorax, and diaphragm
  • Clinically relevant hepatic dysfunction (especially Child Pugh C)
  • Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m^2 e.g. calculated based on Schwartz formula)
  • PH associated with idiopathic interstitial pneumonia (PH-IIP)

Sites / Locations

  • IPS Centro Médico Imbanaco de Cali S.A.
  • Universitätsklinikum Heidelberg
  • Universitätsklinikum Ulm
  • Deutsches Herzzentrum
  • Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet
  • SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont
  • A.O.U. di Padova
  • Aichi Children's Health and Medical Center
  • National Cerebral and Cardiovascular Center
  • Osaka University Hospital
  • Keio University Hospital
  • Operadora de Hospitales Angeles S. A. de C. V.
  • Instituto Nacional de Cardiología "Ignacio Chávez"
  • Wojewodzki Szpital Specjalistyczny - Wroclaw
  • Veterans General Hospital
  • Hacettepe Universitesi Tip Fakultesi

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Riociguat

Arm Description

Participants with age ≥6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 1.0 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration (up to 0.5 mg) of the dose for safety reasons was allowed at any time.

Outcomes

Primary Outcome Measures

Number of Participants With Any Treatment-emergent Adverse Events
An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a participant administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs).
Change in Heart Rate From Baseline
Mean change in heart rate from baseline is reported.
Change in Blood Pressure From Baseline
Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.
Change in Respiratory Rate From Baseline
Mean change in respiratory rate from baseline is reported.
Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age
X-ray of left hand was performed for each participant and bone age was determined centrally by a specialist. For each participant, the bone age was compared to the chronological age and assigned to one of the categories - "delayed", "in accordance" or "advanced", indicating the advancement or delay in the growth of the bone. Number of participants who transitioned to another category different from baseline was calculated and is reported.
Change in Hematology Parameters (Platelets) From Baseline
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Sodium) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (eGFR) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. eGFR = estimated glomerular filtration rate
Change in Clinical Chemistry (Urea) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Plasma Concentration of Riociguat at Week 0
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week.
Plasma Concentration of Riociguat at Week 4
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Plasma Concentration of Riociguat at Week 8
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Plasma Concentration of BAY60-4552 at Week 0
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week
Plasma Concentration of BAY60-4552 at Week 4
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Plasma Concentration of BAY60-4552 at Week 8
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.

Secondary Outcome Measures

Change in 6-minute Walking Distance From Baseline
6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility.
Number of Subjects With Change in WHO Functional Class From Baseline
The World Health Organization (WHO) functional class describes how severe a patient's pulmonary hypertension (PH) symptoms are. There are four different classes - I is the mildest and IV the most severe form of PH. Number of participants per change in number of classes is reported.
Change in NT-proBNP From Baseline
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
Change in BNP From Baseline
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline
SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored using nom-based scoring to produce physical and psychosocial health summary measures. The possible range for the physical measure is -10.9 to 57.2 scores and the possible range for the psychosocial measure is 8.8 to 62.3 scores. Higher scores indicate more favorable functioning.
Change in Quality of Life Evaluated by PedsQL Scale
The PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score (23 questions), physical health summary score (physical functioning, 8 questions) and psychosocial health summary score (emotional, social and school functioning, 15 questions). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life.
Number of Subjects With Clinical Worsening
Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott's anastomosis and atrioseptostomy, worsening of pulmonary arterial hypertension (PAH) symptoms, which must include either an increase in World Health Organization (WHO) functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy.
Change in Estimated Right Atrial Pressure From Baseline
Estimated right atrial pressure was measured by echocardiography.
Change in Left Ventricular Eccentricity Index From Baseline
Left ventricular (LV) eccentricity index (EI) was measured by echocardiography and defined as the ratio of the LV anteroposterior dimension to the septolateral dimension in the parasternal short-axis window by echocardiography. The value of EI greater than 1.0 is abnormal and suggests right ventricle (RV) overload.
Change in Pericardial Effusion From Baseline
Pericardial effusion was measured by echocardiography.
Change in Pulmonary Artery Acceleration Time From Baseline
Pulmonary artery acceleration time was measured by echocardiography.
Change in Right Ventricular Cardiac Index From Baseline
Right ventricle (RV) cardiac index (CI) was measured by echocardiography and calculated by dividing the cardiac output (stroke volume × heart rate) by the body surface area. The change in RV CI should not be understood solely but associated with other conditions of the participants.
Change in Right Ventricular Cardiac Output From Baseline
Right ventricular cardiac output was measured by echocardiography.
Change in Right Atrial Diastolic Area From Baseline
Right atrial diastolic area was measured by echocardiography.
Change in Right Atrial Diastolic Area Index From Baseline
Right atrial (RA) diastolic area index was measured by echocardiography and calculated by dividing the RA area at end-diastole by the body surface area. The RA area index is a reflection of RA volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.
Change in Right Atrial Systolic Area From Baseline
Right atrial systolic area was measured by echocardiography.
Change in Right Atrial Systolic Area Index From Baseline
Right atrial (RA) systolic area index was measured by echocardiography and calculated by dividing the RA area at end-systole by the body surface area. The RA area index is a reflection of RA volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.
Change in Right Ventricular Fractional Area Change From Baseline
Right ventricular fractional area change was measured by echocardiography.
Change in Right Ventricular Diastolic Area From Baseline
Right ventricular diastolic area was measured by echocardiography.
Change in Right Ventricular Diastolic Area Index From Baseline
Right ventricular (RV) diastolic area index was measured by echocardiography and calculated by dividing the RV area at end-diastole by the body surface area. The RV area index is a reflection of RV volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.
Change in Right Ventricular Systolic Area From Baseline
Right ventricular systolic area was measured by echocardiography.
Change in Right Ventricular Systolic Area Index From Baseline
Right ventricular (RV) systolic area index was measured by echocardiography and calculated by dividing the RV area at end-systole by the body surface area. The RV area index is a reflection of RV volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.
Change in Systolic Pulmonary Artery Pressure From Baseline
Systolic pulmonary artery pressure was measured by echocardiography.
Change in Tricuspid Annular Plane Systolic Excursion From Baseline
Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.
Change in Tricuspid Regurgitation Peak Velocity From Baseline
Tricuspid regurgitation peak velocity was measured by echocardiography.

Full Information

First Posted
September 28, 2015
Last Updated
September 27, 2023
Sponsor
Bayer
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02562235
Brief Title
Riociguat in Children With Pulmonary Arterial Hypertension (PAH)
Acronym
PATENT-CHILD
Official Title
Open-label, Individual Dose Titration Study to Evaluate Safety, Tolerability and Pharmacokinetics of Riociguat in Children From 6 to Less Than 18 Years of Age With Pulmonary Arterial Hypertension (PAH)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 29, 2015 (Actual)
Primary Completion Date
March 7, 2020 (Actual)
Study Completion Date
January 27, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study was designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of riociguat at age-, sex- and body-weight-adjusted doses of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID in children from ≥6 to less than 18 years with pulmonary arterial hypertension (PAH) group 1. The study design consisted of a main study part followed by an optional long-term extension part. The main treatment period consisted of two phases: titration phase up to 8 weeks and a maintenance phase up to 16 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Pulmonary
Keywords
Pulmonary arterial hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Riociguat
Arm Type
Experimental
Arm Description
Participants with age ≥6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 1.0 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration (up to 0.5 mg) of the dose for safety reasons was allowed at any time.
Intervention Type
Drug
Intervention Name(s)
Riociguat (Adempas, BAY63-2521)
Intervention Description
For children with body-weight <50 kg at screening: body-weight adjusted dose equivalent to the exposure of (0.5 mg) 1.0 - 2.5 mg three times a day, IDT in adults treated for PAH; oral suspension. For children ≥50 kg at screening: 1.0 to 2.5 mg three times a day; oral tablet.
Primary Outcome Measure Information:
Title
Number of Participants With Any Treatment-emergent Adverse Events
Description
An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a participant administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs).
Time Frame
From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
Title
Change in Heart Rate From Baseline
Description
Mean change in heart rate from baseline is reported.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Blood Pressure From Baseline
Description
Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Respiratory Rate From Baseline
Description
Mean change in respiratory rate from baseline is reported.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Number of Subjects With Transitions From Baseline in Bone Age Compared to Chronological Age
Description
X-ray of left hand was performed for each participant and bone age was determined centrally by a specialist. For each participant, the bone age was compared to the chronological age and assigned to one of the categories - "delayed", "in accordance" or "advanced", indicating the advancement or delay in the growth of the bone. Number of participants who transitioned to another category different from baseline was calculated and is reported.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Hematology Parameters (Platelets) From Baseline
Description
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Hematology Parameters (Lymphocytes/Leucocytes Ratio) From Baseline
Description
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Hematology Parameter (Neutrophils/Leucocytes Ratio) From Baseline
Description
Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Alanine Aminotransferase) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Aspartate Aminotransferase) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Sodium) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Blood Urea Nitrogen) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (eGFR) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set. eGFR = estimated glomerular filtration rate
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Urea) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Clinical Chemistry (Gamma Glutamyl Transferase) From Baseline
Description
Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline are reported in this data set.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Plasma Concentration of Riociguat at Week 0
Description
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week.
Time Frame
Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
Title
Plasma Concentration of Riociguat at Week 4
Description
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Time Frame
Week 4 (pre-dose)
Title
Plasma Concentration of Riociguat at Week 8
Description
For each participant, one blood sample was collected at one given time point. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Time Frame
Week 8 (pre-dose)
Title
Plasma Concentration of BAY60-4552 at Week 0
Description
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported. W = Week
Time Frame
Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
Title
Plasma Concentration of BAY60-4552 at Week 4
Description
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Time Frame
Week 4 (pre-dose)
Title
Plasma Concentration of BAY60-4552 at Week 8
Description
BAY60-4552 is riociguat's active metabolite. For each participant, one blood sample was collected at one given time point and in that sample both riociguat and BAY60-4552 were measured. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics. Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) are reported.
Time Frame
Week 8 (pre-dose)
Secondary Outcome Measure Information:
Title
Change in 6-minute Walking Distance From Baseline
Description
6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Number of Subjects With Change in WHO Functional Class From Baseline
Description
The World Health Organization (WHO) functional class describes how severe a patient's pulmonary hypertension (PH) symptoms are. There are four different classes - I is the mildest and IV the most severe form of PH. Number of participants per change in number of classes is reported.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in NT-proBNP From Baseline
Description
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in BNP From Baseline
Description
Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the participants. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Quality of Life Evaluated by SF-10 Questionnaire From Baseline
Description
SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored using nom-based scoring to produce physical and psychosocial health summary measures. The possible range for the physical measure is -10.9 to 57.2 scores and the possible range for the psychosocial measure is 8.8 to 62.3 scores. Higher scores indicate more favorable functioning.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Quality of Life Evaluated by PedsQL Scale
Description
The PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score (23 questions), physical health summary score (physical functioning, 8 questions) and psychosocial health summary score (emotional, social and school functioning, 15 questions). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Number of Subjects With Clinical Worsening
Description
Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott's anastomosis and atrioseptostomy, worsening of pulmonary arterial hypertension (PAH) symptoms, which must include either an increase in World Health Organization (WHO) functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy.
Time Frame
Up to Week 24 (plus/minus 5 days)
Title
Change in Estimated Right Atrial Pressure From Baseline
Description
Estimated right atrial pressure was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Left Ventricular Eccentricity Index From Baseline
Description
Left ventricular (LV) eccentricity index (EI) was measured by echocardiography and defined as the ratio of the LV anteroposterior dimension to the septolateral dimension in the parasternal short-axis window by echocardiography. The value of EI greater than 1.0 is abnormal and suggests right ventricle (RV) overload.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Pericardial Effusion From Baseline
Description
Pericardial effusion was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Pulmonary Artery Acceleration Time From Baseline
Description
Pulmonary artery acceleration time was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Cardiac Index From Baseline
Description
Right ventricle (RV) cardiac index (CI) was measured by echocardiography and calculated by dividing the cardiac output (stroke volume × heart rate) by the body surface area. The change in RV CI should not be understood solely but associated with other conditions of the participants.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Cardiac Output From Baseline
Description
Right ventricular cardiac output was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Atrial Diastolic Area From Baseline
Description
Right atrial diastolic area was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Atrial Diastolic Area Index From Baseline
Description
Right atrial (RA) diastolic area index was measured by echocardiography and calculated by dividing the RA area at end-diastole by the body surface area. The RA area index is a reflection of RA volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Atrial Systolic Area From Baseline
Description
Right atrial systolic area was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Atrial Systolic Area Index From Baseline
Description
Right atrial (RA) systolic area index was measured by echocardiography and calculated by dividing the RA area at end-systole by the body surface area. The RA area index is a reflection of RA volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Fractional Area Change From Baseline
Description
Right ventricular fractional area change was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Diastolic Area From Baseline
Description
Right ventricular diastolic area was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Diastolic Area Index From Baseline
Description
Right ventricular (RV) diastolic area index was measured by echocardiography and calculated by dividing the RV area at end-diastole by the body surface area. The RV area index is a reflection of RV volume at end-diastole. The change in the index should not be understood solely but associated with other conditions of the participants.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Systolic Area From Baseline
Description
Right ventricular systolic area was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Right Ventricular Systolic Area Index From Baseline
Description
Right ventricular (RV) systolic area index was measured by echocardiography and calculated by dividing the RV area at end-systole by the body surface area. The RV area index is a reflection of RV volume at end-systole. The change in the index should not be understood solely but associated with other conditions of the participants.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Systolic Pulmonary Artery Pressure From Baseline
Description
Systolic pulmonary artery pressure was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Tricuspid Annular Plane Systolic Excursion From Baseline
Description
Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Title
Change in Tricuspid Regurgitation Peak Velocity From Baseline
Description
Tricuspid regurgitation peak velocity was measured by echocardiography.
Time Frame
Baseline and Week 24 (plus/minus 5 days)
Other Pre-specified Outcome Measures:
Title
Taste and Texture (Questions 1 to 4) of the Oral Suspension of Riociguat at Week 0
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
Time Frame
At the beginning of the treatment (Week 0)
Title
Taste and Texture (Questions 1 to 4) the Oral Suspension of Riociguat at Week 24
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 are reported in this endpoint. Questions 1 and 2 were asked before the participants received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Participants were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
Time Frame
Week 24 (plus/minus 5 days)
Title
Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 0
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
Time Frame
At the beginning of the treatment (Week 0)
Title
Taste and Texture (Question 5) of the Oral Suspension of Riociguat at Week 24
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 5 "Taste of the drink" is reported in this endpoint. Question 5 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
Time Frame
Week 24 (plus/minus 5 days)
Title
Taste and Texture (Question 6) of the Oral Suspension of Riociguat at Week 0
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
Time Frame
At the beginning of the treatment (Week 0)
Title
Taste and Texture (Question 6) of the Oral Suspension of Riociguat in Mouth at Week 24
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 6 "Drink feels in mouth" is reported in this endpoint. Question 6 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
Time Frame
Week 24 (plus/minus 5 days)
Title
Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 0
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
Time Frame
At the beginning of the treatment (Week 0)
Title
Taste and Texture (Question 7) of the Oral Suspension of Riociguat in Mouth at Week 24
Description
To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of participants per responses to Questions 7 "Did you like the taste after swallowing" is reported in this endpoint. Question 7 was only asked to participants who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Participants were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
Time Frame
Week 24 (plus/minus 5 days)
Title
Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 0
Description
The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".
Time Frame
At the beginning of the treatment (Week 0)
Title
Expression Assessment on the Taste and Texture of Oral Suspension of Riociguat - Week 24
Description
The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".
Time Frame
Week 24 (plus/minus 5 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Children from 6 years to less than 18 years of age with pulmonary arterial hypertension (PAH) Diagnosed with PAH : Idiopathic (IPAH) Hereditable (HPAH) PAH associated with (APAH) Connective tissue disease Congenital heart disease with shunt closure more than 6 months ago (no open shunts, confirmed by RHC no less than 4 months after surgery) Regardless of the type of PAH, the following findings are not exclusionary: --- Patent foramen ovale (PFO) and asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 cm (both confirmed by echocardiogram) and not associated with hemodynamic alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 are not exclusionary PAH diagnosed by right heart catheterization (RHC) at any time prior to enrolment (for patients with closed shunts - RHC no less than 4 months after surgery) PAH confirmed by a RHC at any time prior to start of study, with mean pulmonary artery pressure (PAPmean) ≥25 mmHg at rest, pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >240 dyn•sec•cm^-5 (i.e., ≥3.0 wood units•m^2) Patients must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit. Two groups of patients will be included: Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) who need additional treatment (discretion of the investigator) Incident: Treatment naïve patients initiated on PAH medication (allowing ERA and /or PCA) and then riociguat added once patients are stable on standard of care WHO functional class I-III Adolescent females of childbearing potential can only be included in the study if a pregnancy test is negative. Adolescent females of childbearing potential must agree to receive sexual counseling and use effective contraception as applicable. 'Effective contraception' is defined as progestogen-only hormonal contraception associated with inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or any combination of adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to use contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration. Young men must agree to use adequate contraception when sexually active. Written inform consent provided and if applicable child assent provided Exclusion Criteria: Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in any form -- Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1. The use of any drug including NO acutely for testing during catheterization is not an exclusion criterion. Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization or any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-adapted level of the 50th SBP percentile (NHBPEP, 2004) History of left-sided heart disease, including valvular disease or heart failure Pulmonary hypertension related to conditions other than specified in the inclusion criteria WHO functional class IV Pulmonary veno-occlusive disease Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 times the upper limit of normal (ULN) Severe restrictive lung disease Severe congenital abnormalities of the lung, thorax, and diaphragm Clinically relevant hepatic dysfunction (especially Child Pugh C) Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m^2 e.g. calculated based on Schwartz formula) PH associated with idiopathic interstitial pneumonia (PH-IIP)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
Facility Name
IPS Centro Médico Imbanaco de Cali S.A.
City
Cali
State/Province
Valle Del Cauca
ZIP/Postal Code
760042
Country
Colombia
Facility Name
Universitätsklinikum Heidelberg
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Universitätsklinikum Ulm
City
Ulm
State/Province
Baden-Württemberg
ZIP/Postal Code
89075
Country
Germany
Facility Name
Deutsches Herzzentrum
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet
City
Budapest
ZIP/Postal Code
1096
Country
Hungary
Facility Name
SZTE ÁOK Szent Györgyi Albert Klinikai Kozpont
City
Szeged
ZIP/Postal Code
6720
Country
Hungary
Facility Name
A.O.U. di Padova
City
Padova
State/Province
Veneto
ZIP/Postal Code
35128
Country
Italy
Facility Name
Aichi Children's Health and Medical Center
City
Obu
State/Province
Aichi
ZIP/Postal Code
474-8710
Country
Japan
Facility Name
National Cerebral and Cardiovascular Center
City
Suita
State/Province
Osaka
ZIP/Postal Code
564-8565
Country
Japan
Facility Name
Osaka University Hospital
City
Suita
State/Province
Osaka
ZIP/Postal Code
565-0871
Country
Japan
Facility Name
Keio University Hospital
City
Shinjuku-ku
State/Province
Tokyo
ZIP/Postal Code
160-8582
Country
Japan
Facility Name
Operadora de Hospitales Angeles S. A. de C. V.
City
Huixquilucan
ZIP/Postal Code
52763
Country
Mexico
Facility Name
Instituto Nacional de Cardiología "Ignacio Chávez"
City
Mexico D.F.
ZIP/Postal Code
14080
Country
Mexico
Facility Name
Wojewodzki Szpital Specjalistyczny - Wroclaw
City
Wroclaw
ZIP/Postal Code
51-124
Country
Poland
Facility Name
Veterans General Hospital
City
Kaohsiung City
ZIP/Postal Code
813414
Country
Taiwan
Facility Name
Hacettepe Universitesi Tip Fakultesi
City
Ankara
ZIP/Postal Code
06100
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.
Links:
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe
URL
https://clinicaltrials.bayer.com/
Description
Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

Learn more about this trial

Riociguat in Children With Pulmonary Arterial Hypertension (PAH)

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